Ethers of morphine and dihydromorphine and their respective nu-oxides



Patented Jan. 4, 1938 PATENT OFFICE ETHER's F MORPHINE. AND DIHYDROMOR;

. sPHINE AND THEIR RESPECTIVE N-OXIDES Lyndon Frederick Small,Charlottesville, Va., as-

signor to The Government of the United States, represented by theSecretary of the v Treasury.

' No Drawing.

Application October 24, 1936, Serial No. 107,466

7 Claims. (01. 260 25) (Granted under, the act of March 3,1883, asamended April 30, 1928; 370 0. G. 757) The invention described hereinmay be manufactured and used by or forthe Government of the United.States for governmental purposes without paymentof any royalty thereon.

The present invention includes ethers of morphine and its dihydrogenatedderivative, dihydromorphine, and the N-oxidesiof these others, in

which the radical taking partin the etherification is of suchnature-thateit protects'the phe- 1 nolic hydroxyl group from undesiredreactions during chemical manipulations, but may at the conclusion ofsuch manipulations be removed by gentle hydrolytic processes toregenerate thephe-' nolic hydroxyl group. in the finalproduct. ,Itfurthe'r. includes the nitrogen oxides of such ethers, wherein thenitrogen at'om is protected from undesired changes during chemicalmanipulations, through addition "of an oxygen atom,

, and wherein the pro-tectingoxygen atom can be removed by reductiveprocesses after suchchem- 'ical manipulations are completed. Theproducts of the invention are in themselves highly active in the animalbody, and may find use'in medical practice, and are furthermore usefulintermediates in the production of the ethers of morphine and. itsdihydrogenated derivative which form the subject matter of mycopending'application for patent, Ser. No. 46,215, filed October 22,1935, patented October 27, 1936, Patent No. 2,058,521.

' Insofar as subject matterof the presentapplication is disclosed insaid application ,Ser. No.

46,215, the present application is a continuation thereof. I V Theinvention comprises the following closely related products? 1. Thehitherto unknown solvated crystalline form ofmethoxymethylmorphine-N-oxide, containing one mole of acetone ofcrystallization.

' 2. The hitherto unknown methoxymethyl ether of dihydromorphine.

3. The nitrogen oxide (amine oxide) derivaof the benzyl ether ofdihydromorphine.

It will be recognized that item 3 might equally wellg'be described asthe methoxymethyl ether of V dihydromorphinemtrogen oxide; that item 4might equally well be described as the benzyl product, isolated byevaporation of'the solvent position C19H25O4N.

6. The nitrogen oxide (amine oxide) derivative ether of morphinenitrogen oxide; and that item 6 might equally well be described as thebenzyl ether-of dihydromorphine nitrogen oxide. Y

The first product of the invention, the memo ym-ethylmorphine nitrogenoxide acetone com- 5 3 pound, is obtained in that the varnish-likeamorphous methoxymethylmorphine nitrogen oxide described by'C. Mannich(see Archiv der Pharmazie, vol. 254, pages 358 and following, of 1916)is treated with successive small amountsof ace- 10, 1

tone, during which the sides of the glass vessel I are rubbed gentlywith a glass rod'until crystallization begins; I Since the purecrystalline compound which separate sis nearly insoluble in acetone,thequantity of this solvent, within reason- 5:3.

able limits, is immaterial. The crystalline product is washedwith warmacetone until the eilluentliquid no longer is yellow in color, wherebysoluble impuritiesare removed. The product consists of snow-whitesparkling crystals, stable 20 in air, which are found by analysis tohave the composition of C19H2304N.C3HsO. "This crystalline productforms, in comparison with the hith-' erto known amorphous impuremethoxymethyltained as follows by two methods:

(a) Pure methoxymethylmorphine, dissolved in a suitable organic solvent,as methanol, ethanol, ethyl acetate etc., but not in acidic'solvents,is' 35 shaken under hydrogen in the presence of a platinum, palladium ornickel catalyst, until about one mole of hydrogen has been absorbed. The

after removal of the catalyst; is best purified 'by crystallization fromacetone. It has the melting point 99-101 C and shows in alcohol solutionthe specific rotation j v (a),i= 1s4.5

(c=1.133). Analysis shows it to have thecorn- Salts ofmethoxymethyldihydromorphine can carried quite to completion, so thatthe reaction.

, mixture always remains slightly'alkaline ,The

hydrochloride I monohydrate, prepared by the use of alcoholichydrogenchloride, has the formula C19H2sO4NC1+HzO,and melts at 124-126 0., withf gas evolution. In aqueous solution it shows the specific rotation Theneutral sulfate pentahydrate has the fore mula Cs3H52O12N2S-l-5H2O,melts at 20l -203 C.;"'

- be mentioned only the hydrochloride monohy- (evacuated tube, gasevolution), and shows in aqueous solution the specific rotation when thewell known dihydromorphine, in the form of its sodium salt, is treatedin chloroform solution with an equivalent amount of chloro- Afterremoval of somethylether, C1CH2OCH3. dium chloride, the chloroform isevaporated, and the product purified as described under (a).

The third product of the invention, the nitrogen oxide derivative ofmethoxymethyldihydromorphine is formed when the alkaloidal basedescribed as the second product of the invention is treated under gentlewarming with a 30% aqueous solution of hydrogen peroxide. After removalof excess hydrogen peroxide in the presence of a catalyst for itsdecomposition, such as metallic platinum, and evaporation of excesswater under diminished pressure, a viscous, varnish-like substance isobtained. The nature of this as the nitrogen oxide derivative ofmethoxymethyldihydromorphine is shown:

(a) By its solubility in water, and its insolubility in diethyl ether;

(b) By its indifference toward such reagents.

of white crystals, which are sparingly soluble in water, but may bepurified from alcohol. The product has the formula C24H25O4N and meltsat 236-238" C., in an evacuated tube, with decomposition. It shows inalcohol the specific rotation The fifth product of the invention, thebenzyl ether of dihydromorphine can be attained as follows by twomethods: 7 e

(a) The well known benzyl ether of morphine, suspended in methanol,ethanol or other suitable organic solvent (dilute acids'may be used, butdo not give as satisfactory results because of partial hydrolysis) isagitated in an atmosphere of hydrogen in the presence of a platinum,palladium or nickel catalyst, until approximately one mole of hydrogenhas been absorbed. The catalyst is removed, and the solutionconcentrated to a small volume, whereupon the benzyldihydromorphineseparates in a crystalline form. It is best purified from about its ownweight of ethyl acetate, from, which it crystallizes as the monohydrate.

It has the melting point -97 C., and the specific rotation in alcohol(0:1.028). Analysis shows the formula to be .C24H2'7O3N-i-H2O. Numeroussalts of the benzyldihydromorphine can be prepared, of which need drate,having the formula C24H28O3NC1+H2O, the melting point 233-235 C., andthe specific rotation (water, 0:0.960) and the perchlorate, having theformula C24H280'INC1, the melting point 188- 192 C., and the specificrotation (alcohol, 0:1.008). V

The sixth product of the invention,'the nitrogen oxide ofdihydromorphine benzyl ether is attained in that the above mentionedbenzyldihydromorphine is dissolved with gentle warming in twice its ownweight of a 30% aqueous solution of hydrogen peroxide, and the resultingsolution is evaporated to dryness under diminished pressure in thepresence of metallic platinum or similar catalyst for the decompositionof excess hydrogen peroxide. The resulting amorphous powdery white solidis the nitrogen oxide of benzyldihydromorphine, as is shown by itsextreme solubility in water, its insolubility in diethyl ether, and byits facile transformation to benzyldihydromorphine through the action ofreducing agents in alkaline, neutral .or weakly acid medium. a a

What I claim as new is:

1. A crystalline molecular compound consisting of one molecularproportion of morphine methoxymethyl ether nitrogen oxide in combinationwith one molecular proportion of acetone, and having the formulaC19H2304N+C3H60.

2. A morphine derivative in which the alicyclic double bond present inthe metho-xymethyl ether of morphine has been saturated by the additionof two hydrogen atoms, as wellas salts of such derivative. 7 V

3. A dihydromorphine derivative in which an oxygen atom has been addedto the tertiary nitrogen atom present in the methoxymethyl ether ofdihydromorphine.

4. A morphine derivative in which an oxygen atom has been added to thetertiary nitrogen atom present in the benzyl ether of morphine, andwhich has the formula C24H2504N.

5. A morphine derivative in which the alicyclic unsaturation present inthe benzyl ether of morphine has been saturated by the addition of twohydrogen atoms, as well as salts of such derivative.

6. A dihydromorphine derivative in which an oxygen atom has been addedto the tertiary nitrogen atom present in the benzyl ether ofdihydromorphine.

'l. A dihydromorphine derivative in which the hydrogen atom of thephenolic hydroxyl group of dihydromorphine has been replaced by aprotective group easily split therefrom when desired, said protectivegroup being selected from the class consisting of methoxymethyl andbenzyl radicals and their analogs, as well as the salts of suchderivative.

LYNDON FREDERICK SMALL.

